This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to its deposition in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed xcex2 amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Axcex2 is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, xcex2 secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and xcex3 secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other xcex2 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of xcex2 APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3 secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or ysecretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein Q, R2, R3, R5, R5a, R6, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Axcex2.
Thus, in one embodiment, the present invention provides a novel compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C2-C6 alkynyl substituted with 0-3 R1a;
C3-C10 cycloalkyl substituted with 0-3 R1b;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; or
5 to 10 membered heterocycle substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, R1b, Cl, F, Br, I, OR14, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 haloalkyl; C1-C4 haloalkoxy;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 10 membered heterocycle substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
C2-C6 alkenyl substituted with 0-2 R1c;
C2-C6 alkynyl substituted with 0-2 R1c;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, NR19R20, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle substituted with 0-3 R1f;
R1d, at each occurrence, is independently selected from H,
C1-C6 alkyl substituted with 0-3 R1e;
C2-C6 alkenyl substituted with 0-2 R1e;
C2-C6 alkynyl substituted with 0-2 R1e;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f;
5 to 10 membered heterocycle substituted with 0-3 R1f;
R1e, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f;
5 to 10 membered heterocycle substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;
R2 is H, C1-C6 alkyl, (C1-C6 alkoxy) C1-C3 alkyl, C3-C6 carbocycle, C6-C10 aryl, (C3-C6 carbocycle)methyl, (C6-C10 aryl)methyl, (C6-C10 aryl)ethyl, or 5 to 10 membered heterocycle;
R5 is H, OH, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
alternatively, R5 and R5a may be combined to form xe2x95x90R5;
alternatively, R5 and R5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R5c;
optionally the cycloalkyl ring formed by combining R5 and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; and
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H,
C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, aryl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is a 5 to 10 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains a heteroatom selected from xe2x80x94Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(R10)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, and xe2x80x94S(xe2x95x90O)2xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form C3-C6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S;
wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-2 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 cycloalkyl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-2 R12;
C2-C4 alkenyl substituted with 0-2 R12;
C2-C4 alkynyl substituted with 0-2 R12;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b; C3-C10 carbocycle substituted with 0-4 R12b; or 5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19b, at each occurrence, is independently selected from H, C1-C4 alkyl, phenyl, benzyl, and phenethyl; and
R20 and R21, at each occurrence, are independently selected from H, C1-C4 alkyl, aryl, and aryl(C1-C2 alkyl)xe2x80x94.
[1] In another embodiment, the present invention provides a novel compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is C1-C6 alkyl substituted with 0-3 R1a;
C3-C10 cycloalkyl substituted with 0-3 R1b;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, R1b, Cl, F, Br, I, OR14, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 haloalkyl; C1-C4 haloalkoxy;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
C2-C6 alkenyl substituted with 0-2 R1c;
C2-C6 alkynyl substituted with 0-2 R1c;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, NR19R20, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1d, at each occurrence, is independently selected from H,
C1-C6 alkyl substituted with 0-3 R1e;
C2-C6 alkenyl substituted with 0-2 R1e;
C2-C6 alkynyl substituted with 0-2 R1e;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1e, at each occurrence, is independently selected from H, OR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, OR14, SR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R2 is H, C1-C6 alkyl, (C1-C6 alkoxy) C1-C3 alkyl, C3-C6 carbocycle, C6-C10 aryl, (C3-C6 carbocycle)methyl, (C6-C10 aryl)methyl, (C6-C10 aryl)ethyl, or 5 to 10 membered heterocycle;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5a is H or C1-C4 alkyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16; acetyl, xe2x80x94S(C1-C4 alkyl), xe2x80x94S(xe2x95x90O)(C1-C4 alkyl), xe2x80x94S(xe2x95x90O)2(C1-C4 alkyl);
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, aryl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is a 6, 7, or 8 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains a heteroatom selected from xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94N(R10)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, and
additionally, two R11 substituents on adjacent atoms may be combined to form C3-C6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S;
wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)xe2x80x94R17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-2 R10a;
C6-C11 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 cycloalkyl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 RXb;
RXb at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
alternatively, xe2x80x94NR15R16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19b, at each occurrence, is independently selected from H, C1-C4 alkyl, phenyl, benzyl, and phenethyl; and
R20 and R21, at each occurrence, are independently selected from H, C1-C4 alkyl, aryl, and aryl(C1-C2 alkyl)xe2x80x94;
provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl, or octyl; R2 is H; R5 is methyl, and xe2x80x94WXYZ is methyl, then Ring B is not 
wherein R13 is H.
[2] In an alternative embodiment of the present invention of of Formula (I),
Q is C1-C6 alkyl substituted with 0-3 R1a;
C3-C10 cycloalkyl substituted with 0-3 R1b;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, R1b, Cl, F, Br, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OR14, Cl, F, Br, NO2, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, OR1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, OR14, Cl, F, Br, NO2, NR19R20, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy; xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1d, at each occurrence, is independently selected from H, C1-C6 alkyl, and C6-C10 aryl substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, OR14, SR14, Cl, F, Br, I, CN, NO2, xe2x95x90O, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R2 is H or C1-C6 alkyl;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b; or
C2-C6 alkynyl substituted with 0-3 R5b;
R5a is H or C1-C4 alkyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16; acetyl, S(C1-C4 alkyl), S(xe2x95x90O)(C1-C4 alkyl), S(xe2x95x90O)2(C1-C4 alkyl),
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R6 is H, methyl, or ethyl;
Ring B is a seven membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains a heteroatom selected from xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94N(R10)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, and xe2x80x94S(xe2x95x90O)2xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form C3-C6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S;
wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-2 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
X is a bond;
phenyl substituted with 0-3 RXb;
C3-C6 cycloalkyl substituted with 0-3 RXb; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, or xe2x80x94C(xe2x95x90O)NHxe2x80x94;
Z is H;
C1-C6 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, and C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
alternatively, xe2x80x94NR15R16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R20 is H or C1-C4;
provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl, or octyl; R2 is H; R5 is methyl, and xe2x80x94WXYZ is methyl, then Ring B is not 
wherein R13 is H.
[3] In another alterantive embodiment of the present invention of of Formula (I),
Ring B is selected from: 
wherein each benzo fused radical is substituted with 0-3 R13.
[4] In another alternative embodiment of the present invention of of Formula (I),
Q is C1-C6 alkyl substituted with 0-3 R1a;
C3-C10 cycloalkyl substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, Cl, F, Br, NR19R20, CF3, C1-C4 alkyl; C1-C4 haloalkyl;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OR14, Cl, F, Br, NO2, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O) R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d,
xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d,
NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d,
xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, OR14, Cl, F, Br, NO2, NR19R20, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy; xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C3-C10 cycloalkyl substituted with 0-3 R1f;
C3-C10 carbocycle substituted with 0-3 R1f;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1d, at each occurrence, is independently selected from H, C1-C6 alkyl, and C6-C10 aryl substituted with 0-3 R1f;
R1f at each occurrence, is independently selected from H, Cl, F, Br, NO2, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R2 is H, methyl, or ethyl;
R5 is OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b; or
C2-C6 alkynyl substituted with 0-3 R5b;
R5a is H or C1-C4 alkyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, acetyl, xe2x80x94S(C1-C4 alkyl), S(xe2x95x90O)(C1-C4 alkyl), S(xe2x95x90O)2(C1-C4 alkyl);
C3-C10 cycloalkyl substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R6 is H;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, phenyl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
X is a bond;
phenyl substituted with 0-3 RXb;
C3-C6 cycloalkyl substituted with 0-3 RXb; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C6 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, CN, NO2, and CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl,benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-6 alkyl);
alternatively, xe2x80x94NR15R16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R20 is H or C1-C4;
provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl, or octyl; R2 is H; R5 is methyl, and xe2x80x94WXYZ is methyl, then Ring B is not 
wherein R13 is H.
[5] In another alternative embodiment of the present invention of of Formula (I),
Ring B is 
Q is C1-C6 alkyl substituted with 0-2 R1a;
C6-C10 aryl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, Cl, F, Br, NR19R20, CF3, C1-C4 alkyl, C1-C4 haloalkyl, and phenyl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OR14, Cl, F, Br, NO2, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy; xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
C6-C10 aryl substituted with 0-3 R1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, and xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
R1d, at each occurrence, is independently selected from H, C1-C6 alkyl, and C6-C10 aryl substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, Cl, F, Br, NO2, CF3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 is OR14;
C1-C6 alkyl substituted with 0-1 R5b;
C2-C6 alkenyl substituted with 0-1 R5b; or
C2-C6 alkynyl substituted with 0-1 R5b;
R5a is H or C1-C4 alkyl;
R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16; acetyl, xe2x80x94S(C1-C4 alkyl), xe2x80x94S(xe2x95x90O)(C1-C4 alkyl), xe2x80x94S(xe2x95x90O)2(C1-C4 alkyl), C3-C7 cycloalkyl substituted with 0-3 R5c;
phenyl substituted with 0-3 R5c; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, xe2x80x94NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, metrhoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R11, at each occurrence, is independently selected from H, xe2x80x94NR18R19, xe2x80x94C(xe2x95x90O)R17, xe2x80x94C(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)NR18R19, xe2x80x94S(xe2x95x90O)2NR18R19, xe2x80x94CF3;
C1-C6 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, CN, NO2, NR15R16, CF3, phenyl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
X is a bond;
phenyl substituted with 0-3 RXb;
C3-C6 cycloalkyl substituted with 0-3 RXb; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, methyl, and ethyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C6 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C3 alkyl, C1-C3 alkoxy, Cl, F, Br, CN, NO2, and CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, and C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl,benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
alternatively, xe2x80x94NR15R16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
R17 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R20 is H, methyl, ethyl, propyl, or butyl.
[6] In another alternative embodiment of the present invention of of Formula (I),
Ring B is 
Q is C1-C6 alkyl substituted with 0-1 R1a;
phenyl substituted with 0-3 R1b;
naphthyl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, Cl, F, Br, xe2x80x94NR19R20, xe2x80x94CF3; and phenyl substituted with 0-3 R1b;
R1b at each occurrence, is independently selected from H, methyl, ethyl, OR14, Cl, F, Br, NO2, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy;
xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
phenyl substituted with 0-3 R1f; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, and xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d;
R1d, at each occurrence, is independently selected from H, C1-C6 alkyl; and phenyl substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, Cl, F, Br, NO2, CF3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is OR14 or C1-C4 alkyl substituted with 0-1 R5b;
R5a is H;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, xe2x80x94NR15R16;
C3-C7 cycloalkyl substituted with 0-3 R5c;
phenyl substituted with 0-3 R5c; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R5c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, xe2x80x94NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)2CH3, methyl, and methoxy;
R11, at each occurrence, is independently selected from H, NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NO2, NR15R16, CF3, phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is xe2x80x94(CHR8)pxe2x80x94;
p is 0 or 1;
R8 is H, methyl, or ethyl;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-3 RXb; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Y is a bond, xe2x80x94Vxe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94Vxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C6 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, NO2, or CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH3CH2C(xe2x95x90O)xe2x80x94, CH3C(xe2x95x90O)xe2x80x94, CH3CH20C(xe2x95x90O)xe2x80x94, CH30C(xe2x95x90O)xe2x80x94, CH3CH2S(xe2x95x90O)2xe2x80x94 and CH3S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl; and
R20 is H, methyl, ethyl, propyl, or butyl.
[7] In another alternative embodiment of the present invention of of Formula (I),
Ring B is 
Q is C1-C4 alkyl substituted with 0-1 R1a;
phenyl substituted with 0-3 R1b;
naphthyl substituted with 0-3 R1b; or
5 to 10 membered heterocycle containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1b; wherein said 5 to 10 membered heterocycle is selected from pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, imidazolyl, oxazolyl, and isoxazolyl;
R1a, at each occurrence, is independently selected from H, Cl, F, Br, CF3, and phenyl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, methyl, ethyl, OR14, Cl, F, Br, NO2, NR19R20, CF3, OCF3, C1-C4 alkoxy, C1-C4 haloalkoxy; xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d, xe2x80x94C(xe2x95x90O)Oxe2x80x94R1d, xe2x80x94OC(xe2x95x90O)xe2x80x94R1d;
C1-C6 alkyl substituted with 0-3 R1c;
phenyl substituted with 0-3 R1f; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1f;
R1c, at each occurrence, is independently selected from H, xe2x80x94C(xe2x95x90O)xe2x80x94R1d, xe2x80x94Oxe2x80x94R1d, xe2x80x94Sxe2x80x94R1d, xe2x80x94S(xe2x95x90O)xe2x80x94R1d, xe2x80x94S(xe2x95x90O)2xe2x80x94R1d, xe2x80x94N(R19)xe2x80x94R1d, xe2x80x94C(xe2x95x90O)NR19bR1d, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94R1d, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94R1d, and xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94R1d,
R1d, at each occurrence, is independently selected from H, C1-C6 alkyl; and phenyl substituted with 0-3 R1f;
R1f, at each occurrence, is independently selected from H, Cl, F, Br, NO2, CF3, xe2x80x94OCF3, methyl, ethyl, methoxy, and ethoxy;
R5 is methyl substituted with 0-1 R5b;
ethyl substituted with 0-1 R5b;
propyl substituted with 0-1 R5b; or
butyl substituted with 0-1 R5b;
R5a is H;
R5b, at each occurrence, is independently selected from: H, methyl, ethyl, and NR15R16;
R11, at each occurrence, is independently selected from H, NR18R19, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, methoxy, and ethoxy;
W is a bond, xe2x80x94CH2xe2x80x94, or xe2x80x94CH(CH3)xe2x80x94;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-3 RXb; or
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl;
Y is a bond, xe2x80x94Vxe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C6 alkyl substituted with 0-2 R12;
C2-C6 alkenyl substituted with 0-2 R12;
C2-C6 alkynyl substituted with 0-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR15R16, CF3, OCF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from H, methyl, methoxy, Cl, F, Br, and CF3;
R14 at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl; and
R20 is H, methyl, ethyl, propyl, or butyl.
[8] In another alternative embodiment of the present invention of of Formula (I),
Q is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, phenyl-, 4-tBu-phenyl-, 4-iPr-phenyl-, 4-Et-phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 2-Cl-phenyl-, 3-Cl-phenyl-, 4-Cl-phenyl-, 2-Br-phenyl-, 3-Br-phenyl-, 4-Br-phenyl-, 2-NO2-phenyl-, 3-NO2-phenyl-, 4-NO2-phenyl-, 2-CH3-phenyl-, 3-CH3-phenyl-, 4-CH3-phenyl-, 2-CH3O-phenyl-, 3-CH3O-phenyl-, 4-CH3O-phenyl-, 2-CF3-phenyl-, 3-CF3-phenyl-, 4-CF3-phenyl-, 2-CF3O-phenyl-, 3-CF3O-phenyl-, 4-CF3O-phenyl-, 2-CH3CONH-phenyl, 3-CH3CONH-phenyl, 4-CH3CONH-phenyl, 2-methyoxycarbonyl-phenyl-, 4-phenyl-phenyl-, 2,3-diF-phenyl-, 2,4-diF-phenyl-, 2,5-diF-phenyl-, 2,6-diF-phenyl-, 3,4-diF-phenyl-, 3,5-diF-phenyl-, 2,3-diCl-phenyl-, 2,4-diCl-phenyl-, 2,5-diCl-phenyl-, 2,6-diCl-phenyl-, 3,4-diCl-phenyl-, 3,5-diCl-phenyl-, 3-F-4-Cl-phenyl-, 3-F-5-Cl-phenyl-, 3-Cl-4-F-phenyl-, 2,3-diMe-phenyl-, 2,4-diMe-phenyl-, 2,5-diMe-phenyl-, 2,6-diMe-phenyl-, 3,4-diMe-phenyl-, 3,5-diMe-phenyl-, 2,3-diMeO-phenyl-, 2,4-diMeO-phenyl-, 2,5-diMeO-phenyl-, 2,6-diMeO-phenyl-, 3,4-diMeO-phenyl-, 3,5-diMeO-phenyl-, 2,3-diCF3-phenyl-, 2,4-diCF3-phenyl-, 2,5-diCF3-phenyl-, 2,6-diCF3-phenyl-, 3,4-diCF3-phenyl-, 3,5-diCF3-phenyl-, 2-NO2-4-CF3-phenyl-, 2-Me-5-Cl-phenyl-, 2,4,6-triMe-phenyl, benzyl-, naphth-1-yl-, naphth-2-yl-, beta-styrene-, furanyl-, thienyl-, pyridyl-, thiazolyl-, imidazol-1-yl-, oxazolyl-, isoxazolyl-, quinolin-8-yl-, 3-methyl-isoxazol-4-yl-, 3,5-dimethyl-isoxazol-4-yl-, 3-bromo-5-chloro-thiophen-2-yl-, 2,3-dichlorothiophen-5-yl-, 4-bromo-5-chlorothiophen-2-yl-, 5-[(benzoylamino)methyl]-thiophen-2-yl-, 4-phenylsulfonylthiophen-2-yl-, 5-(phenylsulfonyl)thiophen-2-yl-, 2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophen-5-yl-, 5-(2-pyridyl)thiophen-2-yl-, 1-methyl-5-(trifluoromethyl)imidazol-3-yl-, 2-(2-methylthio-pyrimdin-3-yl)-thiophen-5-yl-, or dibenzofuran-2-yl-;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, cyclopentyl-CH2xe2x80x94, cyclohexyl-CH2xe2x80x94, (2-CH3-cyclopropyl)CH2xe2x80x94, (3-CH3-cyclobutyl)CH2xe2x80x94, cyclopropyl-CH2CH2xe2x80x94, cyclobutyl-CH2CH2xe2x80x94, cyclopentyl-CH2CH2xe2x80x94, cyclohexyl-CH2CH2xe2x80x94, (2-CH3-cyclopropyl)CH2CH2xe2x80x94, (3-CH3-cyclobutyl)CH2CH2xe2x80x94, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, furanyl-CH2xe2x80x94, thienyl-CH2xe2x80x94, pyridyl-CH2xe2x80x94, 1-imidazolyl-CH2xe2x80x94, oxazolyl-CH2xe2x80x94, isoxazolyl-CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2-, (4-F-phenyl)CH2CH2xe2x80x94, furanyl-CH2CH2xe2x80x94, thienyl-CH2CH2xe2x80x94, pyridyl-CH2CH2xe2x80x94, 1-imidazolyl-CH2CH2xe2x80x94, oxazolyl-CH2CH2xe2x80x94, or isoxazolyl-CH2CH2xe2x80x94,
W is a bond, xe2x80x94CH2xe2x80x94, or xe2x80x94CH(CH3)xe2x80x94;
X is a bond; 
Y is a bond, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94,
Z is H, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94C(CH3)2CH2CH3, xe2x80x94CH(CH3)CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH2CH3, xe2x80x94CH2CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH2CH(CH3)2, xe2x80x94CH2CH(CH2CH3)2, xe2x80x94CH2CH2C(CH3)3, xe2x80x94CH(CH2CH3)CH2CH2CH3, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CH2CH2CH2CH2CF3, cyclopropyl-, (cyclopropyl)CH2xe2x80x94, (cyclopropyl)CH2CH2xe2x80x94, cyclobutyl-, (cyclobutyl)CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94, cyclopentyl-, (cyclopentyl)CH2xe2x80x94, (cyclopentyl)CH2CH2xe2x80x94, cyclohexyl-, (cyclohexyl)CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino, N-piperidinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl)CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94, (thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, morpholino)CH2xe2x80x94, (N-piperidinyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (phenyl)2CHCH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2CH2xe2x80x94, (2-MeO-phenyl)CH2CH2xe2x80x94, (3-MeO-phenyl)CH2CH2xe2x80x94, (4-MeO-phenyl)CH2CH2xe2x80x94, (2-Me-phenyl)CH2CH2xe2x80x94, (3-Me-phenyl)CH2CH2xe2x80x94, (4-Me-phenyl)CH2CH2xe2x80x94, (2-MeS-phenyl)CH2CH2xe2x80x94, (3-MeS-phenyl)CH2CH2xe2x80x94, (4-MeS-phenyl)CH2CH2xe2x80x94, (2-CF3O-phenyl)CH2CH2xe2x80x94, (3-CF3O-phenyl)CH2CH2xe2x80x94, (4-CF3O-phenyl)CH2CH2xe2x80x94, (furanyl)CH2CH2xe2x80x94, (thienyl)CH2CH2xe2x80x94, (pyridyl)CH2CH2xe2x80x94, (2-Me-pyridyl)CH2CH2xe2x80x94, (3-Me-pyridyl)CH2CH2xe2x80x94, (4-Me-pyridyl)CH2CH2xe2x80x94, (imidazolyl)CH2CH2xe2x80x94, (oxazolyl)CH2CH2xe2x80x94, (isoxazolyl)CH2CH2xe2x80x94, (benzimidazolyl)CH2CH2xe2x80x94, (cyclopropyl)CH2CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94, (cyclopentyl)CH2CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, (morpholino)CH2CH2xe2x80x94, or (N-piperidinyl)CH2CH2xe2x80x94;
R11, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH3-phenyl, 4-CF3-phenyl, 4-CH3O-phenyl, 4-CF3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH3-phenyl, 3-CF3-phenyl, 3-CH3O-phenyl, 3-CF3O-phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-CH3-phenyl, 2-CF3-phenyl, 2-CH3O-phenyl, 2-CF3O-phenyl, (4-F-phenyl)methyl-, (4-Cl-phenyl)methyl-, (4-CH3-phenyl)methyl-, (4-CF3-phenyl)methyl-, (4-CH3O-phenyl)methyl-, (4-CF3O-phenyl)methyl-, (3-F-phenyl)methyl-, (3-Cl-phenyl)methyl-, (3-CH3-phenyl)methyl-, (3-CF3-phenyl)methyl-, (3-CH3O-phenyl)methyl-, (3-CF3O-phenyl)methyl-, (2-F-phenyl)methyl-, (2-Cl-phenyl)methyl-, (2-CH3-phenyl)methyl-, (2-CF3-phenyl)methyl-, (2-CH3O-phenyl)methyl-, (2-CF3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 1-piperidinyl, 1-homopiperidinyl, and 1-morpholino; and
R13, at each occurrence, is independently selected from H, F, Cl, and methoxy.
[9] In another alternative embodiment of the present invention of of Formula (I),
Q is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, phenyl-, 2-F-phenyl-, 2-Cl-phenyl-, 2-Br-phenyl-, 2-NO2-phenyl-, 2-CH3-phenyl-, 2-CH3CH2-phenyl-, 2-CH3O-phenyl-, 2-CF3-phenyl-, 2-CF3O-phenyl-, 2-CH3CONH-phenyl, or 3,5-dimethyl-isoxazol-4-yl-;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2,
W is a bond, xe2x80x94CH2xe2x80x94, or xe2x80x94CH(CH3)xe2x80x94;
X is a bond; 
Y is a bond, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94,
Z is H, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94C(CH3)2CH2CH3, xe2x80x94CH(CH3)CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH2CH3, xe2x80x94CH2CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH2CH(CH3)2, xe2x80x94CH2CH(CH2CH3)2, xe2x80x94CH2CH2C(CH3)3, xe2x80x94CH(CH2CH3)CH2CH2CH3, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CH2CH2CH2CH2CF3, cyclopropyl-, (cyclopropyl)CH2xe2x80x94, (cyclopropyl)CH2CH2xe2x80x94, cyclobutyl-, (cyclobutyl)CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94, cyclopentyl-, (cyclopentyl)CH2xe2x80x94, (cyclopentyl)CH2CH2xe2x80x94, cyclohexyl-, (cyclohexyl)CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino, N-piperidinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl)CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94, (thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, morpholino)CH2xe2x80x94, (N-piperidinyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (phenyl)2CHCH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2CH2xe2x80x94, (2-MeO-phenyl)CH2CH2xe2x80x94, (3-MeO-phenyl)CH2CH2xe2x80x94, (4-MeO-phenyl)CH2CH2xe2x80x94, (2-Me-phenyl)CH2CH2xe2x80x94, (3-Me-phenyl)CH2CH2xe2x80x94, (4-Me-phenyl)CH2CH2xe2x80x94, (2-MeS-phenyl)CH2CH2xe2x80x94, (3-MeS-phenyl)CH2CH2xe2x80x94, (4-MeS-phenyl)CH2CH2xe2x80x94, (2-CF3O-phenyl)CH2CH2xe2x80x94, (3-CF3O-phenyl)CH2CH2xe2x80x94, (4-CF3O-phenyl)CH2CH2xe2x80x94, (furanyl)CH2CH2xe2x80x94, (thienyl)CH2CH2xe2x80x94, (pyridyl)CH2CH2xe2x80x94, (2-Me-pyridyl)CH2CH2xe2x80x94, (3-Me-pyridyl)CH2CH2xe2x80x94, (4-Me-pyridyl)CH2CH2xe2x80x94, (imidazolyl)CH2CH2xe2x80x94, (oxazolyl)CH2CH2xe2x80x94, (isoxazolyl)CH2CH2xe2x80x94, (benzimidazolyl)CH2CH2xe2x80x94, (cyclopropyl)CH2CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94, (cyclopentyl)CH2CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, (morpholino)CH2CH2xe2x80x94, or (N-piperidinyl)CH2CH2xe2x80x94;
R11, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH3-phenyl, 4-CF3-phenyl, 4-CH3O-phenyl, 4-CF3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH3-phenyl, 3-CF3-phenyl, 3-CH3O-phenyl, 3-CF3O-phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-CH3-phenyl, 2-CF3-phenyl, 2-CH3O-phenyl, 2-CF3O-phenyl, (4-F-phenyl)methyl-, (4-Cl-phenyl)methyl-, (4-CH3-phenyl)methyl-, (4-CF3-phenyl)methyl-, (4-CH3O-phenyl)methyl-, (4-CF3O-phenyl)methyl-, (3-F-phenyl)methyl-, (3-Cl-phenyl)methyl-, (3-CH3-phenyl)methyl-, (3-CF3-phenyl)methyl-, (3-CH3O-phenyl)methyl-, (3-CF3O-phenyl)methyl-, (2-F-phenyl)methyl-, (2-Cl-phenyl)methyl-, (2-CH3-phenyl)methyl-, (2-CF3-phenyl)methyl-, (2-CH3O-phenyl)methyl-, (2-CF3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 1-piperidinyl, 1-homopiperidinyl, and 1-morpholino; and
R13, at each occurrence, is independently selected from H, F, Cl, and methoxy.
[10] In another alternative embodiment, the present invention provides a novel compound of Formula (Ic): 
or a pharmaceutically acceptable salt form or prodrug thereof.
[11] In another alternative embodiment, the present invention provides a novel compound of Formula (Id): 
or a pharmaceutically acceptable salt form or prodrug thereof.
[12] In another alternative embodiment, the present invention provides a novel compound of Formula (Ia); 
or a pharmaceutically acceptable salt or prodrug thereof.
[13] In another alternative embodiment of the present invention of Formula (I), R5 is OR14.
[14] In another alternative embodiment of the present invention of Formula (I), R5 is C1-C4 alkoxy substituted with 0-3 R5b.
[15] In a preferred embodiment the present invention provides compound of Formula (I), (Ia), (Ic), or (Id) wherein Q is 3,5-dimethyl-isoxazol-4-yl-.
In a preferred embodiment Q is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, phenyl-, 2-F-phenyl-, 2-Cl-phenyl-, 2-Br-phenyl-, 2-NO2-phenyl-, 2-CH3-phenyl-, 2-CH3CH2-phenyl-, 2-CH3O-phenyl-, 2-CF3-phenyl-, 2-CF3O-phenyl-, 2-CH3CONH-phenyl, or 3,5-dimethyl-isoxazol-4-yl-.
In a preferred embodiment Q is a substituted phenyl as disclosed herein (preferably ortho substituted) or a 5 to 6 membered heterocyclic ring as disclosed herein (preferably substituted); for example, 2-F-phenyl-, 2-Cl-phenyl-, 2-Br-phenyl-, 2-NO2-phenyl-, 2-CH3-phenyl-, 2-CH3CH2-phenyl-, 2-CH3O-phenyl-, 2-CF3-phenyl-, 2-CF3O-phenyl-, 2-CH3CONH-phenyl, or 3,5-dimethyl-isoxazol-4-yl-.
In a preferred embodiment Q is not a trihalomethyl group, preferrably not trifluoromethyl.
In a preferred embodiment when R5 and/or R5a form an alkyl or alkeneyl moiety, optionally substituted, of five carbons or less, then Q is not a haloalkyl, preferably not trifluoromethyl.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.
[16] In another alternative embodiment, the present invention provides a compound selected from:
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
2-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(5-dimethylamino naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(naphthalene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2-acetamido-4-methylthiazole-5-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(thiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(quinoline-8-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2,5-dichlorophenyl sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(mesitylene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-fluorophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-chlorophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-acetamidophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-methoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-tert-butylphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(p-toluene-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(benzyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(beta-styrene-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-((2-methoxycarbonyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2-nitro-4-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2,5-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3,4-dichlorophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-(trifluoromethoxy)phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3,4-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3,5-bis(trifluoromethyl)phenyl-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-ethylphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-isopropylphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2,5-dichlorothiophene-3-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2,3-dichlorothiophene-5-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-bromo-5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(5-[(benzoylamino)methyl]-thiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(4-phenylsulfonylthiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(5-(phenylsulfonyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-[2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophene-5-sulfonylamino]-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(5-(2-pyridyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid [5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide;
N-[1-(3xe2x80x2-Chloro-4xe2x80x2-fluoro-biphenyl-3-ylmethyl)-2-oxo-azepan-3-yl]-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
2-(2-fluoro-benzenesulfonylamino)-N-[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-(2-trifluoromethyl-benzenesulfonylamino)-propionamide;
2-(2-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
4-methyl-2-(2-trifluoromethyl-benzenesulfonylamino)-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid (7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid [5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid (1-methyl-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-[(3,5-dimethyl-isoxazole-4-sulfonyl)-methyl-amino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
3-dimethylamino-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
N-[1-methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-(propane-1-sulfonylamino)-propionamide;
N-(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid [5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide; and
2-methanesulfonylamino-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method for the treatment of neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention provides a method for the treatment of neurological disorders associated with Axcex2 amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention provides a method for the treatment of Alzheimer""s Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention provides a method for the treatment of Alzheimer""s Disease associated with Axcex2 amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention provides a method for for inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
In another embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer""s Disease.
In another embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer""s Disease.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is:
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2 amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex3 secretase, generating the N-terminus of Axcex2, xcex3 secretase cleaving around the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R1a, R2, R13 etc.) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R1a, then said group may optionally be substituted with up to three R1a groups and R1a at each occurrence is selected independently from the definition of R1a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group is xe2x80x9cC1-C4 alkylxe2x80x9d wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl, are specifically preferred. As used herein, xe2x80x9cC1-C3 alkylxe2x80x9d, whether a terminal substituent or a alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred example of xe2x80x9cC3-C10 carbocyclexe2x80x9d or xe2x80x9cC3-C6 carbocyclexe2x80x9d is C3-C6 cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(xe2x95x90O)CH3, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
The term xe2x80x9camino acidxe2x80x9d as used herein, refers to natural, modified or unnatural amino acids of either D- or L-configuration and means an organic compound containing both a basic amino group and an acidic carboxyl group. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Irg Leu, Lys, Met, Orn, Phe, Phe(4-fluoro), Pro, Sar, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose.
The phrase xe2x80x9cadditional lactam carbonsxe2x80x9d, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I). Formula (Ia): 
represents the lactam ring B of Formula (I). Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. Examples of lactam ring B include: 
but are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13; even more preferred examples of lactam ring B are B1 and B6. Preferred examples of substituent R10 or R11 on lactam ring B are methyl, ethyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH3-phenyl, 4-CF3-phenyl, 4-CH3O-phenyl, 4-CF3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH3-phenyl, 3-CF3-phenyl, 3-CH3O-phenyl, 3-CF3O-phenyl, (4-F-phenyl)methyl-, (4-Cl-phenyl)methyl-, (4-CH3-phenyl)methyl-, (4-CF3-phenyl)methyl-, (4-CH3O-phenyl)methyl-, (4-CF3O-phenyl)methyl-, (3-F-phenyl)methyl-, (3-Cl-phenyl)methyl-, (3-CH3-phenyl)methyl-, (3-CF3-phenyl)methyl-, (3-CH3O-phenyl)methyl-, (3-CF3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, and 4-pyridyl-. More preferred examples of substituent R10 or R11 on lactam ring B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-trifluorophenyl)methyl, 2-pyridyl-, 3-pyridyl-, and 4-pyridyl-. The fused rings on lactam ring B may optionally be substituted with R13, wherein the preferred examples of substituent R13 on fused rings of lactam B are methyl, fluoro, chloro, and methoxy.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (Ixe2x80x3) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (Ixe2x80x3) is considered part of the invention. Examples of such configuration include, 
but are not intended to be limited to these examples of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atom to which R5 is attached may display superior biological activity over the opposite enantiomer. For example, where R5 is not H, then the configuration of the carbon may be described as R or S. All configurations are considered part of the invention.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or acetamide, formamide, benzamide, and N-oxide derivatives of amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Compounds of Formula (I) of the present invention can be synthesized by the method of Scheme 1 comprising: step 1, an amino acid coupling; followed by step 2, a deprotection; followed by step 3, a sulfonyl coupling (see Scheme 1). In the method of Scheme 1, a W-X-Y-Z-substituted aminolactam, X, is coupled with a protected natural or unnatural amino acid, XI, to form a compound, XII. The amino protecting group of XII is then removed using a standard deprotection procedure to give a compound XIII. The compound XIII is coupled with an activated sulfonylating agent, XIV, preferably a sulfonyl chloride Qxe2x80x94SO2Cl, XIVa, to form a compound of Formula I. 
In an example of the method of Scheme 1, the coupling of Bob-Alaine to the racemic 3-amino-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one followed by TFA-mediated removal of the Boc group provides the Alanine-substituted lactam 2b (Scheme 1a). Sulfonamide formation using 3,5-Dimethyl-isoxazole-4-sulfonyl chloride and triethylamine as base provides the compound of Example 2. 
Alternatively, compounds of Formula I can be prepared by the method of Scheme 2 which comprises a sequence of sulfonyl coupling, followed by deprotection, followed by amino acid coupling. In the method of Scheme 2, an amino acid derivative which has a protected carboxyl group, XV, is first coupled with a sulfonylating agent (Q)SO2Cl, XIV, or an equivalent activated sulfonylating agent, to form a sulfonamide XVI. The carboxyl protecting group of XVI is removed using a standard deprotection method to give a sulfonamide carboxylic acid XVII. The W-X-Y-Z-substituted aminolactam, X, is then coupled with the sulfonamide carboxylic acid, XVII, to form a compound of Formula I. 
Methods for the synthesis of lactam intermediates as contemplated by the present invention useful in the synthesis of compounds of Formula (I), including amino benzodiazepinones, dibenzo azepinones and other related heterocycles, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, WO 00/07995, and WO 00/38618, which are hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239; Sherrill et al, J. Org. Chem., 1995, 60, 730-734; and Walsh, D. A., Synthesis, September 1980, p.677; and Brown, et al., Tetrahedron Letters, 1971, 8, 667-670.
Synthetic approaches to substituted benzodiazepines are widely described in the literature. The typical methods are illustrated by, but are not limited to, the following references: M. G. Bock et al J. Org. Chem. 1987, 52, 3232. (b) R. G. Sherrill et al J. Org. Chem. 1995, 60, 734. (c) M. G. Bock et al J. Med. Chem. 1989, 32, 13-16. (d) J. L. Castro et al J. Med. Chem. 1997, 40, 2491-2501. (e) M. S. Chambers et al Bioorg. and Med. Chem. Lett. 1993, 3 (10), 1919-1924. (f) J. H. Gogerty et al J. Med. Chem. 1977, 20 (7), 952. (g) G. Semple et al Bioorg. and Med. Chem. Lett. 1996, 6(1), 51-54. (h) G. Semple et al J. Med. Chem. 1997, 40, 331-341. (i) G. Semple et al Bioorg. and Med. Chem. Lett. 1996, 6 (1), 55-58. (j) G. Semple et al Synth. Commun. 1996, 26 (4), 721-727. (k) G. A. Showell et al J. Med. Chem. 1994, 37, 719-721. General synthetic descriptions of 2-aminobenzophenone with various substitutions used in the preparation of benzodiaepines may be found in D. A. Walsh Synthesis 1980, 677.
Incorporation of alpha-alkoxy amino acids provides access to additional compounds. alpha-Alkoxy amino acid derivatives are available from a number of procedures available in the art. For instance, they may be synthesized by electrochemical oxidation of malonic acid half esters in alcoholic solvents as shown in Horikawa, Hiroshi; Iwasaki, Tameo; Matsumoto, Kazuo; Miyoshi, Muneji. A new synthesis of 2-alkoxy- and 2-acetoxy-2-amino acids by anodic oxidation. Tetrahedron Lett. 1976, (3), 191-4. Alternative procecures include alkoxide displacement of dichloroacetic acid to form an alpha-halo-alpha-alkoxyacetate, followed by aminolysis as reported in Gross, Hans; Gloede, Joerg; Freiberg, Juergen. alpha-Halo ethers. XXIX. Glyoxylic acid derivatives from chloromethoxyacetic acid or dichloroacetic acid. Ann. Chem., Justus Liebigs (1967), 702 68-74. and similar references.
An example of an L-xcex1-amino-xcex2-thio-xcex5-caprolactam, as shown in Scheme 3, where ring B is the amino lactam of XVIII and J is a sulfur atom has been reported in the literature. See S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9. One skilled in the art can extend this methodology to the synthesis of xcex2-amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art. 
Methods for the alkylation of lactams as contemplated by the present invention in lactam ring B in Formula (I), including amino benzodiazepines and other related heterocycles, are well known in the art. For example, Scheme 4 demonstrates that the lactam nitrogen of compound XIX or other lactam intermediates of the present invention can be alkylated by generating the anion with bases such as LDA, LiHMDS, lithium bis(trimethylsilyl)amide potassium carbonate or sodium hydride in solvents like THF, with or without cosolvents such as DMPU, HMPA or DMF, and reacting this with a variety of groups containing leaving groups (Xxe2x80x3) like bromide, iodide, mesylate or tosylate. Alkylating agents such as xcex1-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698. 
A variety of suitably protected natural and unnatural amino acid derivatives are commercially available or can be prepared by known procedures and can be coupled to the aminolactam of Ring B using standard coupling procedures. Representative procedures for preparation of amino acids include the Strecker amino acid synthesis; the Ugi 4-component coupling reaction; alkylation of glycine benzophenone imine, Seebach""s method (reviewed in O""Donnell, Martin J.; Fang, Zhiqiang; Seebach""s xe2x80x9cSelf-Regeneration of Chiralityxe2x80x9d and related methods for the synthesis of xcex1-amino acids, Hecheng Huaxue (1996), 4(4), 303-316); Schollkopf""s bislactam method, and many others. For a review, see Duthaler, Rudolf O. Recent developments in the stereoselective synthesis of xcex1-amino acids. Tetrahedron (1994), 50(6), 1539-650.
Protection groups for amine funtional group can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene""s book xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, for example, N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. Other protecting groups for amino acids include but are not limited to Boc (tert-butyloxycarbonyl), Fmoc (Fluorenylmethyloxycarbonyl), cBz (Benzyloxycarbonyl), and Alloc (Allyoxycarbonyl). Methods for removing these protecting groups are known to those skilled in the art.
Suitable coupling agents include but are not limited to activating agents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DICI), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) with or without the additive hydroxybenzotriazole (HOBt) or reagents such as HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), which are used in a suitable solvent such as dichloromethane or N,N-dimethylformamide with a suitable base such as diisopropylethylamine, N-methylmorpholine, or triethylamine. Most preferably, the couplings are run using EDC and HOBt as coupling agents with triethylamine as a base in dichloromethane.